The Journal of Experimental Medicine
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Published 16 December 2002. doi:10.1084/jem.20021552
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© Rockefeller University Press, 0022-1007/2002/12/1605/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 12, December 16, 2002 1605-1615
The PAAD/PYRIN-Family Protein ASC Is a Dual Regulator of a Conserved Step in Nuclear Factor {kappa}B Activation Pathways

Christian Stehlik1, Loredana Fiorentino1, Andrea Dorfleutner2, Jean-Marie Bruey1, Eugenia M. Ariza1, Junji Sagara3 and John C. Reed1

1 The Burnham Institute, The Scripps Research Institute, La Jolla, CA 92037
2 Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
3 Department of Molecular Oncology, Research Center on Aging and Adaptation, Shinshu University School of Medicine, Nagano 390-8621, Japan

Address correspondence to John C. Reed, The Burnham Institute, 10901 North Torrey Pines Rd., La Jolla, CA 92037. Phone: 858-646-3140; Fax: 858-646-3194; E-mail: jreed{at}burnham.org

Apoptosis-associated speck-like protein containing a Caspase recruitment domain (ASC) belongs to a large family of proteins that contain a Pyrin, AIM, ASC, and death domain-like (PAAD) domain (also known as PYRIN, DAPIN, Pyk). Recent data have suggested that ASC functions as an adaptor protein linking various PAAD-family proteins to pathways involved in nuclear factor (NF)-{kappa}B and pro-Caspase-1 activation. We present evidence here that the role of ASC in modulating NF-{kappa}B activation pathways is much broader than previously suspected, as it can either inhibit or activate NF-{kappa}B, depending on cellular context. While coexpression of ASC with certain PAAD-family proteins such as Pyrin and Cryopyrin increases NF-{kappa}B activity, ASC has an inhibitory influence on NF-{kappa}B activation by various proinflammatory stimuli, including tumor necrosis factor (TNF){alpha}, interleukin 1ß, and lipopolysaccharide (LPS). Elevations in ASC protein levels or of the PAAD domain of ASC suppressed activation of I{kappa}B kinases in cells exposed to pro-inflammatory stimuli. Conversely, reducing endogenous levels of ASC using siRNA enhanced TNF- and LPS-induced degradation of the IKK substrate, I{kappa}B{alpha}. Our findings suggest that ASC modulates diverse NF-{kappa}B induction pathways by acting upon the IKK complex, implying a broad role for this and similar proteins containing PAAD domains in regulation of inflammatory responses.

Key Words: inflammation • signal transduction • I{kappa}B kinase • monocytes • NF-{kappa}B


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